Melanoma is a tumor of melanocytes, cells that are derived from the neural crest. Although most melanomas arise in the skin, they may also arise from mucosal surfaces or at other sites to which neural crest cells migrate. Melanoma occurs predominantly in adults, and more than half of the cases arise in apparently normal areas of the skin. Early signs in a naevus that would suggest malignant change include darker or variable discoloration, itching, an increase in size, or the development of satellites. Ulcerations or bleeding are later signs. Melanoma in women occurs more commonly on the extremities and in men on the trunk or head and neck, but it can arise from any site on the skin surface.
Prognosis is affected by clinical and histological factors and by anatomic location of the lesion. Thickness and/or level of invasion of the melanoma, mitotic index, tumor infiltrating lymphocytes, and ulceration or bleeding at the primary site affect the prognosis. Microscopic satellites in stage I melanoma may be a poor prognostic histologic factor, but this is controversial (Leon et al., Archives of Surgery 126(2): 1461-1468, 1991). Melanomas arising on the extremities or in women seem to have a better prognosis (Blois et al., Cancer 52(7): 1330-1341, 1983; Clark et al., J. National Cancer Inst. 81(24): 1893-1904, 1989; Slinguff et al., Cancer 70(7): 1917-1927, 1992; Koh, NEJM 325(3): 171-182, 1991; Shumate et al., Am J Surgery 162(4): 315-319, 1991). Clinical staging is based on whether the tumor has spread to regional lymph nodes or distant sites. For disease clinically confined to the primary site, the greater the thickness and depth of local invasion of the melanoma, the higher the chance of lymph node metastases and the worse the prognosis. Melanoma can spread by local extension (through lymphatics) and/or by hematological routes to distant sites. Any organ may be involved by metastases, but lungs and liver are common sites. The risk of relapse may decrease substantially over time, although late relapses are not uncommon.
Melanoma that has not spread beyond the initial site is highly curable. Most of these cases are those tumors that have not invaded beyond the papillary dermis (State II; thickness, 1.0 mm or less). Melanoma that has spread to regional lymph nodes (Stage III) may be curable with wide (2 to 4 cm) excision of the primary tumor and removal of the involved regional lymph nodes (Karakousis et al, Ann Surg Oncol 13: 533-541, 2006; Batch et al, J Clin Oncol. 27(36): 6199-6206, 2009). Melanoma that has spread to distant sites (Stage IV) is infrequently curable with standard therapy, although ipilimumab and vemurafenib both offer survival benefits, and long-term survival is occasionally achieved by resection of metastasis (Overett and Shiu, Cancer 56:1222-1230, 1985).
Melanoma is the fifth most common cancer in men and the sixth most common cancer in women in the United States of America (USA), with an estimated 76,250 new cases and 9,180 deaths expected in 2012 (Siegel et al., CA Cancer J Clin. 62(1): 10-29, 2102). In Europe, the annual incidence of melanoma is somewhat lower than that in the USA, at approximately 7 per 100,000 as compared to 18 per 100,000 in the USA (Ries et al, 2000). In Europe, approximately 83,729 new cases were diagnosed in 2008 and approximately 85,086 new cases were expected in 2010 (GLOBOCAN 2008, 2010). The incidence of melanoma is increasing rapidly worldwide, with a 270% increase in the USA between 1973 and 2002. This increase is the most rapid of any cancer with the exception of lung cancer in women (Jemal et al., CA Cancer J Clin. 56: 106-130, 2006; Ries et al., Cancer 88: 2398-2424, 2000).
Traditional nonsurgical therapies for unresectable or advanced melanoma in adults include, chemotherapy (Dacarbazine, temozolomide, or other agents either alone or in combination), or interleukin-2. Although some regimes produced objective responses, they were usually short-lived. New therapies such as BRAF inhibition (vemurafenib) and immune stimulatory agents (ipilimumab) have shown significant improvement in overall survival compared to control treatments for a limited percentage of patients treated, however toxicity is an issue.
Despite these efforts melanoma is increasing rapidly worldwide. There is a need for additional melanoma treatments. The present invention addresses this need and others.